Benzenesulfonamide compounds

ABSTRACT

A compound of formula (I):                    
     which is useful as a TXA 2  and 5-HT 2  receptor and pharmaceutical compositions containing the same.

The present invention relates to new benzenesulphonamide compounds. Thisapplication is a Divisional of U.S. Ser. No. 09/764,576 filed Jan. 18,2001.

DESCRIPTION OF THE PRIOR ART

Compounds having a benzenesulphonamide chain have been described inApplication EP 864 561 in relation to their NO-yielding character andtheir thromboxane A₂ (TXA₂) receptor antagonist character, as well as inApplication EP 648 741 solely in relation to their TXA₂ receptorantagonist properties.

The compounds of the present invention have a novel structure givingthem a TXA₂ receptor antagonist and 5HT₂ serotonergic receptorantagonist character.

BACKGROUND OF THE INVENTION

Platelet aggregation and vasospasms play an essential role in theetiology and development of atherothrombotic cardiovascular disorders.TXA₂, an arachidonic acid metabolite, and serotonin (5HT), aneurotransmitter, are both powerful vasoconstrictor agents, and are ableto induce or reinforce platelet activation, resulting in the aggregationthereof. The vasoconstrictor and pro-aggregation actions of TXA₂ areeffected through the intermediary of membrane receptors called TPreceptors (Medicinal Research Reviews, 1991, 11, 5, p. 503) while thoseof serotonin are effected via the intermediary of 5HT₁ or 5HT₂ receptors(T.I.P.S., 1991, 121, p. 223). Research strategies pursued with the aimof finding agents that block the production and/or activation of TXA₂have led to the development of selective TP receptor antagonists, ofTXA₂-synthase inhibitors, or of mixed agents that exhibit bothproperties (Medicinal Research Reviews, ibid., T.I.P.S., 1991, 121,158). Like TXA₂, serotonin acts by stimulating platelets and vascularcontractions and its activity is found to be increased inatherothrombotic disorders.

The idea of compounds that oppose both the process that causesthromboxane to become active and the process that causes serotonin tobecome active is extremely useful for the clinician. Such products havethe advantage of offering more complete protection both against theactivation of platelets and against vasospasms. It will thus be possiblefor such products to be used in the treatment of pathologies associatedwith increased activity of TXA₂ and 5-HT especially in the treatment ofatherothrombotic cardiovascular disorders, such as myocardialinfarction, angina pectoris, cerebral vascular accidents, Raynaud'sdisease, and also asthma and bronchospasms, as well as migraine andvenous disorders.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the compounds of formula (I):

wherein:

n is an integer of from 1 to 3 inclusive,

m is an integer of from 0 to 6 inclusive,

R_(a) represents a hydroxy, linear or branched (C₁-C₆)alkoxy, aryloxy orarylalkyloxy group,

R₁ and R₂ represent independently a hydrogen atom, a halogen atom, analkyl group, a linear or branched (C₁-C₆)alkoxy group, a hydroxy groupor a linear or branched (C₁-C₆)perhaloalkyl group,

R₃ represents a hydrogen atom or an alkyl, arylalkyl, cycloalkylalkyl,aryl or cycloalkyl group,

T₁ represents an alkylene, O-alkylene, alkylene—O—or(C₁-C₃)alkylene-O-(C₁-C₃)-alkylene group,

G represents a G₁- or G₁-T₂-A- group wherein:

A represents an aryl group,

T₂ represents a bond or an alkylene, —O-alkylene, alkylene-O- or(C₁-C₃)alkylene-O —(C₁-C₃)alkylene group,

G₁ represents a —NR₄R₅ group wherein R₄ and R₅ represent independently ahydrogen atom, or an alkyl, cycloalkyl, optionally substituted aryl,optionally substituted arylalkyl, cycloalkylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl group,

or G₁ represents a heterocycloalkyl group of formula

having from

5 to 7 ring members, wherein Y represents a nitrogen atom, an oxygenatom or a CH or CH₂ group and R₆ represents a hydrogen atom or an alkyl,cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted arylcarbonyl, optionallysubstituted arylcarbonylalkyl, optionally substituted diarylalkyl,optionally substituted diarylalkenyl, optionally substituted(aryl)(hydroxy)alkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylcarbonylor optionally substituted heteroarylcarbonylalkyl group,

to their enantiomers and diastereoisomers, and also to addition saltsthereof with a pharmaceutically acceptable acid or base,

wherein:

the term “alkyl” denotes a linear or branched chain having from 1 to 6carbon atoms,

the term “alkenyl” denotes a chain having from 2 to 6 carbon atoms andcontaining from 1 to 3 double bonds,

the term “alkylene” denotes a linear or branched divalent groupcontaining from 1 to 6 carbon atoms, unless specified otherwise,

the term “cycloalkyl” denotes a saturated cyclic group containing from 3to 8 carbon atoms,

the term “aryl” denotes a phenyl or naphthyl group,

the term “heteroaryl” denotes a mono- or bi-cyclic group having from 4to 11 ring members that is unsaturated or partially saturated andcontains from 1 to 5 hetero atoms selected from nitrogen, oxygen andsulphur,

the terms “diarylalkyl” and “diarylalkenyl” denote, respectively, alkyland alkenyl groups as defined hereinbefore, substituted by two identicalor different aryl groups as defined hereinbefore,

the term “substituted” relating to aryl, arylalkyl, arylcarbonyl,arylcarbonylalkyl, diarylalkyl, diarylalkenyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl and heteroarylcarbonylalkyl denotesthat the groups in question are substituted in the aromatic moiety byone or more halogen atoms, alkyl groups, linear or branched(C₁-C₆)alkoxy groups, hydroxy groups, cyano groups, nitro groups oramino groups (optionally substituted by one or two alkyl groups),wherein the heteroaryl and heteroarylalkyl groups may also besubstituted by an oxo group.

Amongst the pharmaceutically acceptable acids there may be mentioned,without implying any limitation, hydrochloric, hydrobromic, sulphuric,phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic,glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic,camphoric acid, etc . . .

Amongst the pharmaceutically acceptable bases there may be mentioned,without implying any limitation, sodium hydroxide, potassium hydroxide,triethylamine, tert-butylamine etc . . .

Preferred compounds of the invention are those wherein n is 2.

Other preferred compounds of the invention are those wherein m is 2.

An advantageous embodiment of the invention relates to compounds offormula (I) wherein R₃ represents a hydrogen atom.

Another advantageous embodiment of the invention relates to compounds offormula (I) wherein R_(a) represents a hydroxy group.

In the compounds of formula (I), G₁ preferably represents aheterocycloalkyl group of formula

There may be mentioned, for example, without implying any limitation,the groups piperidine, pyrrole, piperazine . . .

Advantageously, in the groups G₁, R₆ represents a group selected fromalkyl (for example methyl), arylcarbonyl (for example benzoyl),arylcarbonylalkyl (for example benzoyl-methyl), diarylalkenyl (forexample bisphenylmethylene), (aryl)(hydroxy)alkyl (for example(phenyl)(hydroxy)methyl), aryl (for example phenyl), and heteroaryl,each of those groups being optionally substituted in their aromaticmoiety where such a moiety is present. Advantageously, the substituentchosen will be a halogen atom or an alkoxy group.

Amongst the preferred heteroaryl groups there may be mentioned moreespecially the groups 1,2-benzisoxazole, 1,2-benzisothiazole, . . .

An especially advantageous embodiment of the invention relates tocompounds of formula (I) wherein n and m are each 2, R_(a) represents ahydroxy group, R₂ and R₃ each represents a hydrogen atom, R₁ representsa halogen atom, and G₁ represents a heterocycloalkyl group of formula

wherein Y represents a

nitrogen atom or a —CH or CH₂ group, and R₆ is selected from the groupsalky, arylcarbonyl, arylcarbonylalkyl, diarylalkenyl,(aryl)(hydroxy)alkyl, aryl and heteroaryl.

Amongst the preferred compounds of the invention there may be mentionedmore especially3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-{2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid and3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-{[2-(4-methyl-1-piperazinyl)phenoxy]methyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid.

The present invention relates also to a process for the preparation ofthe compounds of formula (I), which process is characterised in thatthere is used as starting material a compound of formula (II):

wherein n, m, R₁, R₂, R₃ and T₁ are as defined for formula (I), R′_(a)represents a linear or branched (C₁-C₆)alkoxy group and X₁ represents aleaving group (for example a halogen atom or a tosyl group),

which, when it is desired to obtain compounds of formula (I) wherein Grepresents a group G₁ as defined for formula (I), is treated in basicmedium with a compound of formula G₁H to yield a compound of formula(I/a):

a particular case of the compounds of formula (I) wherein m, n, R′_(a),R₁, R₂, R₃, T₁ and G₁ are as defined for formula (I),

or which, when it is desired to obtain compounds of formula (I) whereinG represents a group G₁-T₂-A- as defined for formula (I), is treated inbasic medium with a compound of formula HO-T₂-A-G_(R), wherein T₂ and Aare as defined for formula (I) and G_(R) represents a reactive group soselected that it can effect nucleophilic substitution of the leavinggroup X₁ present in the substrate to yield a compound of formula (IV):

wherein m, n, R′_(a), R₁, R₂, R₃, T₁, A and T₂ are as definedhereinbefore,

the hydroxy group of which is converted into a leaving group or into ahalogen atom to yield a compound of formula (V):

wherein m, n, R′_(a), R₁, R₂, R₃, T₁, A and T₂ are as definedhereinbefore and X₂ represents a leaving group (for example a halogenatom or a tosyl group),

which compound of formula (V) is treated in basic medium with a compoundof formula G₁H, G₁ being as defined for formula (I), to yield a compoundof formula (I/b):

a particular case of the compounds of formula (I) wherein m, n, R′_(a),R₁, R₂, R₃, T₁, T₂, A and G₁ are as defined hereinbefore,

which compounds of formulae (I/a) and (I/b) may be subjected tohydrolysis of the ester function, in acid or basic medium according tothe reactive groups present in the molecule, to yield a compound offormula (I/c):

a particular case of the compounds of formula (I) wherein m, n, R₁, R₂,R₃ and T₁ are as defined hereinbefore and G is as defined for formula(I),

which compounds (Ia), (I/b) and (I/c) constitute the totality of thecompounds of formula (I), and:

may, if necessary, be purified according to a conventional purificationtechnique,

are optionally separated into their stereoisomers according to aconventional separation technique,

are converted, if desired, into addition salts with a pharmaceuticallyacceptable acid or base,

wherein, at any moment considered appropriate during the course of theprocess described above, the carboxylic ester function —CO—R′_(a) may behydrolysed to the corresponding acid, which may be converted again to adifferent ester as required by the synthesis.

The present invention relates also to pharmaceutical compositionscomprising as active ingredient one compound of formula (I), on its ownor in combination with one or more pharmaceutically acceptable, inert,non-toxic excipients or carriers.

Amongst the pharmaceutical compositions according to the invention theremay be mentioned more especially those which are suitable for oral,parenteral or nasal administration, tablets or dragées, sublingualtablets, gelatin capsules, lozenges, suppositories, creams, ointments,dermal gels, etc..

The useful dosage varies in accordance with the age and weight of thepatient, the nature and the severity of the disorder and also theadministration route, which may be oral, nasal, rectal or parenteral.Generally, the unit dosage ranges from 0.1 mg to 500 mg for a treatmentof from 1 to 3 administrations per 24 hours.

The following Examples illustrate the invention and do not limit it inany way.

The starting materials employed are known products or products preparedaccording to known procedures.

Preparation A: Methyl3-(3-(bromomethyl)-6-{[(4-chlorophenyl)sulphonyl]amino}-5,6,7,8-tetrahydro-1-naphthyl)propanoate

Step a: Methyl3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-formyl-5,6,7,8-tetrahydro-1-naphthyl)propanoate

2.5 g of a solution of osmium tetroxide (2.5% by weight) in2-methyl-2-propanol, and then 20 g of sodium periodate, are added atambient temperature to a solution of 10 g (23 mmol) of methyl3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-vinyl-5,6,7,8-tetrahydro-1-naphth-yl)propanoate,described in Application EP 864 561, in a mixture of 100 ml of dioxanand 50 ml of water. After stirring for one night at ambient temperature,the solution is filtered and the filtrate is concentrated. The residueobtained is taken up in dichloromethane and washed with water, and theorganic phase is dried and concentrated and then purified bychromatography on silica gel, using as eluant a cyclohexane/ethylacetate mixture (60/40), to yield the expected compound.

Step b: Methyl3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-hydroxymethyl-5,6,7,8-tetrahydro-1-naphthyl)propanoate

1 g (2.6 mmol) of sodium borohydride is added to a solution of 4 g (9.2mmol) of the product described in the above Step in 100 ml of methanol.The reaction mixture is stirred for 30 minutes at ambient temperature.After the addition of a saturated aqueous solution of sodium hydrogencarbonate and evaporation of the majority of the methanol, the reactionmixture is extracted with dichloromethane. The organic phase is driedand concentrated. Purification by chromatography on silica gel, using aseluant an ethyl acetate/cyclohexane mixture (50/50), yields the expectedproduct.

Step c: Methyl3-(3-(bromomethyl)-6-{[(4-chlorophenyl)sulphonyl]amino}-5,6,7,8-tetrahydro-1-naphthyl)propanoate

At ambient temperature, 2.23 g (8.5 mmol) of triphenylphosphine andthen, slowly, a solution of 2.83 g (8.5 mmol) of carbon tetrabromide in25 ml of dichloromethane, are added to a solution of 3.10 g (7.1 mmol)of the product described in the above Step in 50 ml of dichloromethane.After stirring at ambient temperature for one hour, the solvent isevaporated off. Purification by chromatography on silica gel, using aseluant a cyclohexane/ethyl acetate mixture (80/20), yields the expectedproduct.

Preparation B: Methyl3-(3-(3-bromopropyl)-6-{[(4-chlorophenyl)sulphonyl]amino}-5,6,7,8-tetrahydro-1-naphthyl)propanoate

Step a: Tert-butyl3-(7-{[(4-chlorophenyl)sulphonyl]amino}-4-[2-(methoxy-carbonyl)ethyl]-5,6,7,8-tetrahydro-1-naphthyl)-2-propenoate

1.25 g (4 mmol) of tri-o-tolylphosphine, 8.5 ml of triethylamine, 230 mg(1 mmol) of palladium acetate and 9 ml of tert-butyl acrylate are addedto a solution of 10 g (20.5 mmol) of methyl3-(3-bromo-6-{[(4-chlorophenyl)sulphonyl]amino}-5,6,7,8-tetra-hydro-1-naphthyl)propanoate,described in Application EP 864 561, in 250 ml of DMF. The reactionmixture is stirred at 110° C. for 8 hours. The solvent is thenevaporated off, and purification by chromatography on silica gel, usingas eluant a cyclohexane/ethyl acetate mixture (80/20), yields theexpected product.

Step b: Methyl3-([3-(2-tert-butoxycarbonyl)ethyl]-6-{[(4-chlorophenyl)-sulphonyl]amino}-5,6,7,8-tetrahydro-1-naphthyl)propanoate

0.87 g (3.6 mmol) of cobalt chloride hexahydrate, and then, in portions,1.1 g (2.9 mmol) of sodium borohydride, are added to a solution of 7.5 g(14 mmol) of the product described in the above Step in 100 ml ofmethanol. The reaction mixture is stirred for 2 hours at ambienttemperature and then filtered. The solvent is evaporated off, and theresidue is purified by chromatography on silica gel, using as eluant acyclohexane/ethyl acetate mixture (80/20), to yield the expectedproduct.

Step c:3-(7-{[(4-Chlorophenyl)sulphonyl]amino}-4-[2-(methoxycarbonyl)ethyl]-5,6,7,8-tetrahydro-2-naphthyl)propanoicacid

A solution of 6.4 g (12 mmol) of the product described in the above Stepin 50 ml of trifluoroacetic acid is stirred for 12 hours at ambienttemperature. The solvent is then evaporated off and the residue is takenup in ethyl acetate. The organic phase is washed with brine and thendried and evaporated. The product is obtained after purification bychromatography on silica gel with a dichloromethane/methanol mixture(98/2) as eluant.

Step d: Methyl3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-(3-hydroxypropyl)-5,6,7,8-tetrahydro-1-naphthyl)propanoate

9 ml of a 1M solution of BH₃/THF in THF are slowly added, at ambienttemperature, to a solution of 2.8 g (5.2 mmol) of the product describedin the above Step in 80 ml of THF. After stirring the mixture for onenight at ambient temperature, 10 ml of water are added. The majority ofthe solvent is evaporated off, and the residue is taken up in ethylacetate. The organic phase is then washed with brine, dried andevaporated to yield the expected product.

Step e: Methyl3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-(3-bromopropyl)-5,6,7,8-tetrahydro-1-naphthyl)propanoate

The product is obtained in accordance with the procedure described inPreparation A, Step c, using as starting material the compound describedin the above Step.

Preparation C : Methyl3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-({4-[2-(tosyloxy)-ethyl]phenoxy}methyl)-5,6,7,8-tetrahydro-1-naphthyl)propanoate

Step a: Methyl3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-[4-(2-hydroxyethyl)-phenoxymethyl]-5,6,7,8-tetrahydro-1-naphthyl)propanoate

165 mg (4.2 mmol) of sodium hydride (60% in mineral oil), and then asolution of 1.05 g (2.1 mmol) of the product described in Preparation Ain 50 ml of THF and 1.11 g of crown ether C¹⁸⁻⁶, are added to a solutionof 0.58 g (4.2 mmol) of 2-(4-hydroxyphenyl)ethanol in 100 ml of THF. Thereaction mixture is heated at reflux for one hour. The majority of theTHF is evaporated off, and the mixture is hydrolysed, and adjusted to anacid pH using 1N hydrochloric acid. After extraction withdichloromethane, drying and purification by chromatography on silicagel, using as eluant an ethyl acetate/cyclohexane mixture (50/50), theexpected product is obtained.

Step b: Methyl3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-({4-[2-(tosyloxy)-ethyl]phenoxy}methyl)-5,6,7,8-tetrahydro-1-naphthyl)propanoate

1 g (5.4 mmol) of tosyl chloride, and then 0.5 ml of pyridine, are addedto a solution of 0.75 g (1.35 mmol) of the product obtained in the aboveStep in 50 ml of dichloromethane. After stirring at ambient temperaturefor one night, the mixture is washed with 1N hydrochloric acid anddried. After evaporation of the solvent and purification bychromatography on silica gel, using as eluant a cyclohexane/ethylacetate mixture (60/40), the expected product is obtained.

Preparation D: (2,3-Dimethoxy)(4-piperidinyl)methanol

Step a: 1-Benzyl-4-piperidinylcarboxamide

A mixture of 20 g (156 mmol) of isonipecotamide, 32.4 g (234 mmol) ofpotassium carbonate, 2 g (12 mmol) of potassium iodide and 18.6 ml (156mmol) of benzyl bromide in 400 ml of acetonitrile is heated at refluxfor 5 hours. The solvent is evaporated off and the residue is taken upin a dichloromethane/water mixture. After decanting, extracting withdichloromethane, washing the organic phases with brine and drying,removal of the solvent by evaporation yields the expected product.

Step b: 1-Benzyl-4-piperidylcarbonitrile

26 g (119 mmol) of the product described in the above Step are added inportions to a mixture of 83 ml (890 mmol) of phosphorus oxychloride and17 g (290 mmol) of sodium chloride. The mixture is heated at reflux forone hour. After cooling, the reaction mixture is poured into 75 ml ofconcentrated ammonium hydroxide solution. After extraction withdichloromethane, washing the organic phase with water and drying,removal of the solvent by evaporation yields the expected product.

Step c: 1-Benzyl-4-piperidylcarbaldehyde

120 ml of a 1M solution of diisobutylaluminium hydride in hexane areadded, at 0° C., to a solution of 22 g (110 mmol) of the productdescribed in the above Step in 500 ml of THF. The mixture is stirred atambient temperature for 2 hours. After hydrolysis with a 10%hydrochloric acid solution, the mixture is neutralised with aconcentrated aqueous sodium hydroxide solution. After extraction withdiethyl ether, drying, and removal of the solvent by evaporation,purification by chromatography on silica gel, using as eluant acyclohexane/ethyl acetate mixture (50/50), yields the expected product.

Step d: (1-Benzyl-4-piperidyl)(2,3-dimethoxyphenyl)methanol

32.5 ml of a 1.6M solution of n-butyllithium in hexane are added at 0°C. to a solution of 7.07 g (51 mmol) of veratrole in 150 ml of THF.After stirring for 2 hours at 0° C., the reaction mixture is cooled to−78° C. and a solution of 8.6 g (42 mmol) of the product described inthe above Step in 200 ml of THF is added. Stirring is continued for onehour at −78° C. After returning to ambient temperature, the mixture ishydrolysed with water, extracted with ethyl acetate, dried andconcentrated. Purification by chromatography on silica gel, using ethylacetate as eluant, yields the expected product.

Step e: (2,3-Dimethoxyphenyl)(4-piperidyl)methanol

A mixture of 7.5 g (22 mmol) of the product described in the above Step,1.5 g of palladium on carbon (10%) and 5.5 g (87 mmol) of ammoniumformate in 150 ml of methanol and 30 ml of water is heated at reflux forone hour. After returning to ambient temperature and filtration, thesolvent is evaporated off. The residue is taken up in dichloromethaneand treated with 2N sodium hydroxide solution until a pH of 10 isreached. After extraction with dichloromethane, drying and removal ofthe solvent by evaporation, the expected product is obtained.

Preparation E : 2-(4-Methyl-1-piperazinyl)phenol

Step a: Ethyl 4-(2-hydroxyphenyl)-1-piperazinylcarboxylate

15 ml (156 mmol) of ethyl chloroformate are added to a solution of 18 g(100 mmol) of 2-(1-piperazinyl)phenol in 250 ml of dichloromethane.After stirring at ambient temperature for one hour, the mixture ishydrolysed and then extracted with dichloromethane. The organic phase iswashed with a 1N hydrochloric acid solution and dried. Followingconcentration, the residue obtained is recrystallised from ether toyield the expected product.

Step b: Ethyl 4-[2-(tosyloxy)phenyl]-1-piperazinylcarboxylate 25 g (130mmol) of para-toluenesulphonyl chloride and 20 ml of triethylamine areadded at ambient temperature to a solution of 23 g (91 mmol) of theproduct described in the above Step in 100 ml of dichloromethane. Afterstirring for 72 hours at ambient temperature, the solvent is evaporatedoff. Chromatography on silica gel, using as eluant an ethylacetate/cyclohexane mixture (30/70), yields the expected product.

Step c: [2-(4-Methyl-1-piperazinyl)phenol] 4-toluenesulphonate

3 g (79 mmol) of lithium aluminium hydride are added at 0° C. to asolution of 23.2 g (57 mmol) of the product described in the above Stepin 100 ml of THF. The mixture is stirred for 2 hours at ambienttemperature and then hydrolysed. After concentration and extraction withdichloromethane, the organic phase is dried and concentrated to yieldthe expected compound.

Step d: 2-(4-Methyl-1-piperazinyl)phenol

A mixture of 18 g (52 mmol) of the product described in the above Stepand 44 g (785 mmol) of potassium hydroxide in 400 ml of ethanol isheated at reflux for 2 hours. After returning to ambient temperature,the pH is adjusted to 7 using 1N hydrochloric acid. Followingconcentration, the mixture is extracted with dichloromethane and theorganic phase is dried and then concentrated to yield the expectedproduct.

Preparation F: 4-(4-Methyl-1-piperazinyl)phenol

The product is obtained in accordance with the procedure described inPreparation E, with the replacement of 2-(1-piperazinyl)phenol with4-(1-piperazinyl)phenol in Step a.

EXAMPLE 13-(6{[(4-Chlorophenyl)sulphonyl]amino}-3-{2-4-(4-fluorobenzoyl)-1-piperidinyl]ethyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

Stade a: Methyl3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-{2-[4-(4-fluoro-benzoyl)-1-piperidinyl]ethyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoate

6.5 g (17.3 mmol) of 4-(4-fluorobenzoyl)piperidine tosylate and 2.4 g(17.3 mmol) of potassium carbonate are added to a solution of 3.5 g (5.7mmol) of methyl3-[6-{[(4-chlorophenyl)sulphonyl]amino}-3-(2-{[(4-methylphenyl)sulphonyl]oxy}ethyl)-5,6,7,8-tetrahydro-1-naphthyl]propanoate,described in Application EP 864 561, in 100 ml of DMF. The reactionmixture is heated at reflux for one hour, then concentrated. The residueis taken up in dichloromethane and washed with water. The organic phaseis dried and concentrated and then purified by chromatography on silicagel, using as eluant a dichloromethane/methanol/ammonia mixture(98/2/0.2), to yield the expected compound.

Stade b:3-(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

A solution of 2.2 g (3.5 mmol) of the product described in the aboveStep is heated at reflux for two hours in the presence of 3.5 ml of 2Nsodium hydroxide solution. The reaction mixture is filtered and thefiltrate is concentrated. 100 ml of water are added and the pH isadjusted to 5 using acetic acid. The precipitate formed is then filteredoff and recrystallised from dichloromethane to yield the title compound.

Melting point: 210° C.

Elemental microanalysis:

C % H % N % S % Calculated: 63.20 5.79 4.47 5.11 Found: 62.89 5.87 4.464.82

EXAMPLE 23-[6-{[(4-Chlorophenyl)sulphonyl]amino}-3-(2-{4-[(2,3-dimethoxyphenyl)(hydroxy)methyl]-1-piperidinyl}ethyl)-5,6,7,8-tetrahydro-1-naphthyl]propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement in Step a of4-(4-fluorobenzoyl)piperidine tosylate with the compound described inPreparation D.

Elemental microanalysis:

C % H % N % S % Calculated: 62.63 6.46 4.17 4.78 Found: 62.13 7.00 4.174.64

EXAMPLE 33-(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of4-(4-fluorobenzoyl)piperidine tosylate with6-fluoro-3-piperidin-4-ylbenzo[d]isoxazole hydrochloride in Step a.

Melting point: 125° C.

Elemental microanalysis:

C % H % N % S % Calculated: 61.92 5.51 6.56 5.01 Found: 61.33 5.45 6.364.91

EXAMPLE 43-(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of4-(4-fluorobenzoyl)piperidine tosylate with6-fluoro-3-piperidin-4-ylbenzo[d]isothiazole hydrochloride in Step a.

Melting point: 232° C.

Elemental microanalysis:

C % H % N % S % Calculated: 60.40 5.38 6.40 9.77 Found: 60.17 5.36 6.399.50

EXAMPLE 53-(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{2-[4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl]ethyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of4-(4-fluorobenzoyl)piperidine tosylate with3-piperazin-1-ylbenzo[d]isothiazole hydrochloride in Step a.

EXAMPLE 63-(3-(2-{4-[bis(4-Fluorophenyl)methylene]-1-piperidinyl}ethyl)-6-{[(4-chlorophenyl)sulphonyl]amino}-5,6,7,8-tetrahydro-1-naphthyl)-propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of4-(4-fluorobenzoyl)piperidine tosylate withbis(4fluorophenyl)-methylenepiperidine in Step a.

Meltings point: 242° C.

Elemental microanalysis:

C % H % N % S % Calculated: 66.42 5.57 3.97 4.55 Found: 66.27 5.52 4.054.32

EXAMPLE 73-[6{[(4-Chlorophenyl)sulphonyl]amino}-3-(2-{3-[2-(4-fluoro-phenyl)-2-oxoethyl]-1-pyrrolidinyl}ethyl)-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of4-(4-fluorobenzoyl)piperidine tosylate with1-(4-fluorophenyl)-2-pyrrolidin-3-ylethanone hydrochloride in Step a.

Melting point: 143° C.

Elemental microanalysis:

C % H % N % S % Calculated: 63.20 5.79 4.47 5.11 Found: 63.79 5.79 4.524.99

EXAMPLE 83-(6-{[(4-Chlorophenyl)sulphonyl]amino}-2-{2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of methyl3-[6-{[(4-chlorophenyl)sulphonyl]amino}-3-(2-{[(4-methylphenyl)sulphonyl]oxy}ethyl)-5,6,7,8-tetrahydro-1-naphthyl]propanoatewith methyl3-[6-{[(4-chlorophenyl)sulphonyl]amino}-2-(2-{[(4-methylphenyl)sulphonyl]oxy}-ethyl)-5,6,7,8-tetrahydro-1-naphthyl]propanoatedescribed in Application EP 864 561.

Melting point: 223° C.

Elemental microanalysis:

C % H % N % S % Calculated: 63.20 5.79 4.47 5.11 Found: 63.14 5.80 4.565.17

EXAMPLE 93-(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{[4-(4-fluorobenzoyl)-1-piperidinyl]methyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of methyl3-[6-{[(4-chlorophenyl)sulphonyl]amino}-3-(2-{[(4-methylphenyl)sulphonyl]oxy}ethyl)-5,6,7,8-tetrahydro-1-naphthyl]propanoatewith the product described in Preparation A.

Melting point: 147° C.

Elemental microanalysis:

C % H % N % S % Calculated: 62.69 5.59 4.59 5.23 Found: 62.99 5.49 4.485.17

EXAMPLE 103-(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of methyl3-[6-{[(4-chlorophenyl)sulphonyl]amino}-3-(2-{[(4-methylphenyl)sulphonyl]oxy}ethyl)-5,6,7,8-tetrahydro-1-naphthyl]propanoatewith the product described in Preparation B.

Melting point:118° C.

Elemental microanalysis:

C % H % N % S % Calculated: 63.69 5.97 4.37 5.00 Found: 63.55 6.02 4.374.98

EXAMPLE 113-(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{3-[4-(4-fluorobenzoyl)-1-piperazinyl]propyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of methyl3-[6-{[(4-chlorophenyl)sulphonyl]amino}-3-(2-{[(4-methylphenyl)sulphonyl]oxy}ethyl)-5,6,7,8-tetrahydro-1-naphthyl]propanoatewith the product described in Preparation B, and of4-(4-fluorobenzoyl)piperidine tosylate with (4-fluorophenyl)piperazine.

Elemental microanalysis:

C % H % N % Calculated: 59.07 5.89 6.46 Found: 59.10 5.83 6.34

EXAMPLE 123-{6-{[(4-Chlorophenyl)sulphonyl]amino}-3-[(4-{2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl}phenoxy)methyl]-5,6,7,8-tetrahydro-1-naphthyl}propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of methyl3-[6-{[(4-chlorophenyl)sulphonyl]amino}-3-(2-{[(4-methylphenyl)sulphonyl]oxy}ethyl)-5,6,7,8-tetrahydro-1-naphthyl]propanoatewith the product described in Preparation C.

Melting point: 196° C.

Elemental microanalysis:

C % H % N % S % Calculated: 62.52 5.77 3.82 4.37 Found: 64.89 6.29 3.844.34

EXAMPLE 133-(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{[2-(4-methyl-1-piperazinyl)phenoxy]methyl}-5,6,7,8-tetrahydro-1-naphthyl)-propanoicacid

Stade a: Methyl3-(6-{[(4-chlorophenyl)sulphonyl]amino}-3-{[2-(4-methyl-1-piperazinyl)phenoxy]methyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoate

A mixture of 1.30 g (2.6 mmol) of the product described in PreparationA, 0.5 g (2.6 mmol) of the product described in Preparation E, 200 mg(5.2 mmol) of sodium hydride (60% in oil) and 670 mg of crown etherC¹⁸⁻⁶ is heated at reflux for two hours. After cooling the mixture, 2 mlof acetic acid are added and the reaction mixture is concentrated. Theresidue is taken up in dichloromethane and washed with water. Theorganic phase is dried, concentrated and purified by chromatography onsilica gel, using as eluant a dichloromethane/methanol/ammonia mixture(95/5/0.5), to yield the expected product.

Stade b:3-(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{[2-(4-methyl-1-piperazinyl)-phenoxy]methyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Step b of Example 1, using as starting material thecompound described in the above Step.

Melting point: 122° C.

Elemental microanalysis:

C % H % N % S % Calculated: 62.25 6.07 7.02 5.36 Found: 61.52 6.09 6.845.22

EXAMPLE 143-(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{[4-(4-methyl-1-piperazinyl)phenoxy]methyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 13, with the replacement in Step a of the productdescribed in Preparation E with the product described in Preparation F.

Melting point: 148° C.

Elemental microanalysis:

C % H % N % S % Calculated: 62.25 6.07 7.02 5.36 Found: 61.94 6.36 6.665.11

EXAMPLE 153(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{2-[4-(6-fluoro-1,2-benzo[b]thiophen-3-yl)-1-piperidinyl]ethyl}-5,6,7,8-tetrahydro-1-naphthyl)propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of4-(4-fluorobenzoyl)piperidine tosylate with4-(6-fluorobenzo[b]thiophen-3-yl)piperidine hydrochloride in Step a.

Melting point: 140° C.

Elemental microanalysis:

C % H % N % S % Calculated: 62.32 5.54 4.28 9.79 Found: 62.01 5.36 4.289.80

EXAMPLE 163-(6-{[(4-Chlorophenyl)sulphonyl]amino}-3-{2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl}-5,6,7,8-tetrahydro-1-naphthyl)-propanoicacid

The expected product is obtained in accordance with the proceduredescribed in Example 1, with the replacement of4-(4-fluorobenzoyl)piperidine tosylate with6-fluoro-3-piperidin-4-yl-1H-indazole dihydrochloride in Step a.

Melting point: 142° C.

Elemental microanalysis:

C % H % N % S % Calculated: 62.01 5.68 8.77 5.02 Found: 61.98 5.74 8.704.83

PHARMACOLOGICAL STUDY EXAMPLE A

Platelet aggregation in man

Venous blood is obtained from human volunteers who have not takenaspirin for at least 14 days prior to the experiment. The blood isremoved over sodium citrate (0.109 M) (1 vol. of citrate over 9 vol. ofblood). Platelet-rich plasma (PRP) is obtained by centrifugation (20°C.) at 200 g for 10 minutes. The number of platelets is on average250000 PL/mm³. The PRP is stored at room temperature until the test andis used within 2 hours of having been taken. The TXA₂ agonist U46619 isused at a concentration of 1 μM and 5-hydroxytryptamine is used at aconcentration of 10 μM, the latter in the presence of 0.3 μM adenosinediphosphate and 1 μM adrenalin.

The compounds of the invention inhibit platelet aggregation induced bythe TXA₂ agonist as well as that produced by 5-hydroxytryptamine. By wayof example, the IC₅₀ values of the compound of Example 4 are 170 nM and230 nM respectively for the two targets. The values indicate that thecompounds of the invention are powerful platelet anti-aggregants, whichact in a balanced manner on the two activation routes, that of TXA₂ andthat of serotonin.

EXAMPLE B

Pharmaceutical composition

Formulation for the preparation of 1000 tablets each comprising 5 mg ofactive ingredient: compound of Example 4 5 g hydroxypropylmethylcellulose 2 g wheat starch 10 g lactose 100 g magnesium stearate 3g

We claim:
 1. A compound selected from those of formula (I):

wherein: n is 1 to 3 inclusive, m is 0 to 6 inclusive, R_(a) representshydroxy, linear or branched (C₁-C₆)alkoxy, aryloxy or arylalkyloxy, R₁and R₂ represent independently hydrogen, halogen, alkyl, linear orbranched (C₁-C₆)alkoxy, hydroxy or linear or branched(C₁-C₆)perhaloalkyl, R₃ represents hydrogen, alkyl, arylalkyl,cycloalkylalkyl, aryl or cycloalkyl, T₁ represents alkylene, O-alkylene,alkylene-O—or (C₁-C₃)alkylene-O—(C₁-C₃)alkylene, G represents G₁—orG₁—T₂—A—wherein: A represents aryl, T₂ represents a bond or alkylene, Oalkylene, alkylene-O—or (C₁-C₃)alkylene-O—(C₁-C₃)alkylene, the formulaG₁ represents a heterocycloalkyl of the formula

having 5 ring members, wherein Y represents nitrogen, oxygen, CH, or CH₂and R₆ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted arylcarbonyl, optionally substitutedarylcarbonylalkyl, optionally substituted diarylalkyl, optionallysubstituted diarylalkenyl, optionally substituted (aryl) (hydroxy)alkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylcarbonyl or optionallysubstituted heteroarylcarbonylalkyl, its enantiomers anddiastereoisomers, and its addition salts thereof with apharmaceutically-acceptable acid or base, wherein: “alkyl” is a linearor branched chain having 1 to 6 carbon atoms, “alkenyl” is a chainhaving 2 to 6 carbon atoms and 1 to 3 double bonds, “alkylene” is alinear or branched divalent group consisting of 1 to 6 carbon atoms,unless specified otherwise, “cycloalkyl” is a saturated cyclic groupconsisting of 3 to 8 carbon atoms, “aryl” is phenyl or naphthyl,“heteroaryl” is a mono- or bi-cyclic group, having 4 to 11 ring members,that is unsaturated or partially saturated and consists of 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulphur, “diarylalkyl” and“diarylalkenyl” are, respectively, alkyl and alkenyl groups as definedhereinbefore, substituted by two identical or different aryl groups asdefined hereinbefore, “substituted”, as it relates to aryl, arylalkyl,arylcarbonyl, arylcarbonylalkyl, diarylalkyl, diarylalkenyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl and heteroarylcarbonylalkyl, denotesthat the groups in question are substituted in the aromatic moiety byone or more halogen atoms, alkyl groups, linear or branched(C₁-C₆)alkoxy groups, hydroxy groups, cyano groups, nitro groups oramino groups (optionally substituted by one or two alkyl groups),wherein the heteroaryl and heteroarylalkyl groups may also besubstituted by an oxo group.
 2. A compound of claim 1, wherein n is 2.3. A compound of claim 1, wherein m is
 2. 4. A compound of claim 1,wherein R₃ represents hydrogen.
 5. A compound of claim 1, wherein R_(a)represents a hydroxy group.
 6. A compound of claim 1, wherein G₁represents a heterocycloalkyl group of formula


7. A compound of claim 1, which is3-[6-{[(4-chlorophenyl)sulphonyllamino}-3-(2-{3-[2-(4-fluorophenyl)-2-oxoethyl]-1-pyrrolidinyl}ethyl)-5,6,7,8-tetrahydro-1-naphthyl)propanoic acid.
 8. A compound of claim 1, wherein n and m areeach 2, R_(a) represents hydroxy, R₂ and R₃ each represent hydrogen, R₁represents halogen, and G₁ represents a heterocycloalkyl group offormula

wherein Y represents nitrogen, —CH or CH₂ and R₆ is selected from thegroups consisting of alkyl, arylcarbonyl, arylcarbonylalkyl,diarylalkenyl, (aryl)-(hydroxy)alkyl, aryl and heteroaryl.
 9. Apharmaceutical composition useful for treating an animal or human livingbody afflicted with a disease requiring a TXA₂ receptor antagonist and a5-HT₂ receptor antagonist, selected from the group consisting ofatherothrombotic cardiovascular disorders, Raynaud's disease, asthma,bronchospasms, migraine, and venous disorders, comprising as activeprinciple an effective amount of a compound of claim 1 together with oneor more pharmaceutically-acceptable excipients or vehicle.
 10. A methodfor treating an animal or human living body afflicted with a diseaserequiring a TXA₂ receptor antagonist and a 5-HT₂ receptor antagonist,selected from the group consisting of atherothrombotic cardiovasculardisorders, Raynaud's disease, asthma, bronchospasms, migraine, andvenous disorders, comprising the step of administering to the livingbody an amount of a compound of claim 1 which is effective foralleviation of the disease.